Migrane headache afflicts 15-20% (3:1, females/males) of the population and is a major cause of economic loss. Despite its high prevalence and serious economic consequences, its neurophysiologic, metabolic and molecular basis is poorly understood and has been underinvestigated. This program project represents a joint effort by basic and clinical neuroscientists to understand athe biological basis of migraine headache and its treatment. Our program is comprised of 3 projects, plus scientific administrative cores. Each of the projects is a direct extension of ongoing work in the respective investigators's laboratory, Project will determine what kind of natural stimuli are effective in activating peripheral primary afferent neurons in the trigeminal ganglion) and central (in the trigeminal brainstem nuclear complex) neurons that innervate the dural venous sinuses, and whether antimigraine agents can modulate the neural activity. It will also identify higher brain regions participating in the processing of this craniovascular sensation by mapping axonal projection of the central neurons and measuring changes in cortical and subcortical neuronal activity. Project will examine molecular neuropharmacology of antimigraine agents and seeks to establish importance of neuron receptors mediating therapeutic effects of 5-HT1D receptor agonists (sumatriptan, ergot alkaloid) and GABAergic drugs (valproic acid). Project examines circulatory and metabolic mechanisms associated with spontaneous migraine aura and headache in a defined population of MGH subjects. The Scientific Core will support Projects by providing molecular techniques to define those receptor subtypes which constitute an important locus of antimigraine drug actions and by examining the pattern of neuronal activation in the rat brain after noxious dural stimulation using c-fos in situ hybridization as well as 2-deoxyglucose and iodoantipyrine autoradiography. Our program is unique in part, because many of the proposed experiments evolved from animal and human data published by our labs over athe past 15 years. The approach taken is mechanistically-driven, multidisciplinary (e.g., neurophysiology, anatomy, molecular pharmacology), clinically relevant, molecular in orientation (e.g., in situ hybridization, RT-PCR, receptor autoradiography, immunoblots) and incorporates state of the art imaging tools (MR spectroscopy, diffusion, perfusion MRI) to evaluate human brain before and during migraine headache.